EP1033372A1 - Composes possedant une activite antitumorale - Google Patents

Composes possedant une activite antitumorale Download PDF

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Publication number
EP1033372A1
EP1033372A1 EP98954713A EP98954713A EP1033372A1 EP 1033372 A1 EP1033372 A1 EP 1033372A1 EP 98954713 A EP98954713 A EP 98954713A EP 98954713 A EP98954713 A EP 98954713A EP 1033372 A1 EP1033372 A1 EP 1033372A1
Authority
EP
European Patent Office
Prior art keywords
linker
group
paclitaxel
general formula
conjugate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98954713A
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German (de)
English (en)
Other versions
EP1033372A4 (fr
Inventor
Nobutaka Fujii
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Publication of EP1033372A1 publication Critical patent/EP1033372A1/fr
Publication of EP1033372A4 publication Critical patent/EP1033372A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to conjugates which are useful in treating cancer and anticancer agents containing these conjugates as the active ingredient.
  • taxols such as docetaxel and paclitaxel inhibit cell proliferation based on the effects of promoting tubulin polymerization and stabilizing microtubules, thereby showing antitumor activity. Owing to these characteristics, taxols are expected as being useful as anticancer agents with a novel function mechanism. In particular, attempts have been made to clinically apply taxols to remedies for mammary cancer, ovarian cancer and nonsmall cell lung cancer (K.C. Nicolau, Nature, 367, 630 (1994); R.A. Holton. J. Am. Chem. Soc., 116, 1587 (1994); D. Masopaolo, A. Camerman, Y. Luo, G.D. Brayer & N. Camerman, Proc. Natl. Acad. Sci. USA, 92, 6920 (1995); Gan to Kagakuryhoho (Cancer and Chemotherapy) 21(5), 583 (1994)).
  • somatostatin receptor Y. Yamada & S. Kiyono, Saibo Kogaku (Cell Technology), 12(9), 665 (1993); S. Kiyono & Y. Yamada, Naibunpitsugaku no Shinpo (Advances in Endocrinology), 10, 41 (1992)
  • somatostatin derivatives such as octreotide show antitumor activity via the activity of inhibiting tyrosine kinase.
  • Keri et al. recently reported a tumor cell-specific derivative TT232 (Gy. Keri, et al., Biochem. Biophys. Res.
  • bombesin-like peptides have been identified as autocrine growth factors of small cell lung cancer (SCLC) and it is known that receptors of these peptides are overexpressed on SCLC. Accordingly, it is expected that efficacious bombesin antagonists might be useful as anticancer agents specific to SCLC (F. Cuttina, Nature. 316, 823 (1985); D.H. Coy, J. Biol. Chem., 264, 14691 (1989); L.H. Wang, Biochemistry. 29, 616 (1990); D.H. Coy, Eur. J. Pharmacol., 190, 31 (1990)).
  • EABI (E)-alkene-bombesin isostere
  • (E)-alkene type dipeptide isostere N. Fujii, Tetrahedron Lett., 32, 4969 (1991): N. Fujii, J. Chem. Soc., Perkin I, 1995, 1359
  • this substance shows a potent antagonism in the amylase secretion system (M. Wada, Pancreas, 10, 301 (1995); N. Fujii, Peptides 1994, ed. H.L.S. Maia, Escom Science Publishers B.V. (1995), pp. 77-78; K. Fujimoto, Life Sciences, 60, 29 (1997)).
  • cisplatin, carboplatin, etc. as the first-line drugs for SCLC.
  • these drugs still suffer from some problems including side effects and the expression of tolerance thereto.
  • An object of the present invention is to provide drugs with antitumor activity which are useful as remedies for cancer such as digestive system cancer, mammary cancer, ovarian cancer, lung cancer, etc. , more particularly, anticancer agents comprising conjugates wherein a peptide ligand capable of binding specifically to a receptor expressed specifically in tumor cells is covalently bonded to a paclitaxel derivative via a linker.
  • the present invention provides a conjugate wherein one or more compounds with antitumor activity are chemically bonded to a peptide or a pseudopeptide having an affinity for a receptor expressed on tumor cells.
  • X represents
  • the present invention further provides a compound represented by the following general formula (1) or potential tautomers, stereoisomers or optical isomers thereof: X-L-Y (wherein X represents paclitaxel or its derivative; L represents a linker having (a) functional group(s); and Y represents or and * represents a bond to L.
  • the present invention further provides a compound represented by the following general formula (1) or potential tautomers, stereoisomers or optical isomers thereof: X-L-Y (wherein X represents paclitaxel or its derivative; L represents a linker having (a) functional group(s); and Y represents or and * represents a bond to L.
  • compositions with antitumor activity and anticancer agents which contain the compounds represented by the above general formula (1) or potential tautomers, stereoisomers or optical isomers thereof.
  • the receptor expressed on tumor cells is not restricted in type. Examples thereof include somatostatin receptor and bombesin-like peptides receptors.
  • a pseudopeptide having an affinity for a receptor expressed on tumor cells means one wherein one or more amino acid residues in a peptide have been substituted by structure(s) having a structural homology with peptide bond (for example, (E)-alkene isosteres). Those from which amino acid residue(s) have been deleted also fall within this category.
  • one or more compounds with antitumor activity are chemically bonded to a peptide or a pseudopeptide having an affinity for a receptor expressed on tumor cells.
  • the chemical binding manner is not restricted, there may be mentioned, for example, a linker capable of binding both to the peptide or pseudopeptide and the compound with antitumor activity.
  • linker of this type it is possible to use one capable of binding to an amino acid in the peptide or pseudopeptide and to a hydroxyl group in the compound with antitumor activity.
  • Particular examples of such a linker include compounds having two or more carboxyl groups. When a compound having two or more carboxyl groups is used, one carboxyl group forms an amide bond together with an amino acid in the peptide or pseudopeptide, while another carboxyl group forms an ester bond together with a hydroxyl group in the compound with antitumor activity and thus the peptide or pseudopeptide is bonded to the compound with antitumor activity.
  • the compound having two or more carboxyl groups may have other functional groups, so long as the binding of the peptide or pseudopeptide to the compound with antitumor activity is not inhibited thereby.
  • the compound having two or more carboxyl groups include aromatic compounds, aliphatic open-chain compounds, alicyclic compounds and heterocyclic compounds. Among all, aliphatic open-chain compounds are preferable and dicarboxylic acids (in particular, succinic acid and glutaric acid) are still preferable.
  • the paclitaxel derivative represented by X may be an arbitrary one selected from among compounds having the baccatin skeleton and publicly known taxol derivatives having antitumor activity. Among all, docetaxel is particularly preferable therefor.
  • linker L having a functional group is not particularly restricted, so long as it exerts no undesirable effect on the antitumor activity.
  • linker L there may be mentioned, for example, -(CO)-A-(CO)-(wherein A represents an optionally substituted alkylene group having 2 to 4 carbon atoms).
  • substituent in A i.e., an optionally substituted alkylene group having 2 to 4 carbon atoms
  • examples of the substituent in A include linear or branched alkyl groups having 1 to 3 carbon atoms and hydroxyl group.
  • X and L may be bonded to each other in an arbitrary manner without restriction, so long as the object of the present invention can be achieved.
  • the -CO moiety of the linker L having the structure -(CO)-A-(CO)- may be bonded to the 2'-position of X via an ester bond.
  • the -CO moiety of the above-described linker L may be bonded to the 3'-position of X via an amide bond. It is particularly preferable that the -CO moiety of the linker L is bonded to the 2'-position of X via an ester bond.
  • L and Y may be bonded to each other in an arbitrary manner without restriction, so long as the object of the present invention can be achieved.
  • the -CO moiety of the linker L having the structure -(CO)-A-(CO)- may be bonded to the NH-moiety of Y via an amide bond. It is particularly preferable that the -CO moiety of the linker L is bonded to the NH-moiety of the Phe (phenylalanine) residue of Y via an amide bond.
  • Preferable examples of X include paclitaxel and docetaxel.
  • Preferable examples of A include ethylene and trimethylene groups.
  • any group cited in the definition in the general formula (1) is preferable.
  • Y is represented by the above-described general formula TT232, it is particularly preferable that A 1 is a lysine residue.
  • Preferable examples of the compounds represented by the general formula (1) include those having the following structural formulae: (wherein Boc represents a t-butoxycarbonyl group); and (wherein Boc represents a t-butoxycarbonyl group).
  • the compounds represented by the general formula (1) involve these compounds per se as well as the potential tautomers, stereoisomers and optical isomers thereof and mixtures of the same.
  • conjugate according to the present invention wherein one or more compounds with antitumor activity are chemically bonded to a peptide or a pseudopeptide having an affinity for a receptor expressed on tumor cells, can be synthesized, for example, by the following method wherein a compound of general formula (1) is employed.
  • the above-described peptide or pseudopeptide is bonded to a linker.
  • paclitaxel is reacted with succinic anhydride in the presence of pyridine to give a paclitaxel-linker bond-structure wherein succinic anhydride is bonded via an ester bond to paclitaxel.
  • the thus obtained paclitaxel-linker bond-structure is condensed with EABI by, for example, the WSCDI-HOBt method to give the aimed paclitaxel-(linker)-EABI conjugate.
  • conjugates according to the present invention can be synthesized in the same manner by using other combinations.
  • conjugates of the following combinations can be produced by the above-described method.
  • the paclitaxel or its derivative in the general formula (1) can be obtained by a publicly known method adequate for the desired derivative.
  • paclitaxel can be obtained by the method reported by Kingston, D.G.I., Pharmacol. Ther., 52, 1(1992) and the method disclosed in R.A. Holton, European Patent A 400971,1990.
  • docetaxel can be obtained by the method disclosed in Japanese Patent Application Disclosure SHO No. 63-30479 and the method reported by Greene, A.E. et al., J. Org. Chem., 59, 1238 (1994).
  • the peptide or pseudopeptide to be used in the present invention can be obtained by applying publicly known methods for synthesizing peptides, for example, the method of N. Fujii et al. (Tetrahedron Lett., 32, 4969 (1991); J. Chem. Soc., Perkin I, 1995, 1359). It is also possible to obtain the peptide or pseudopeptide via the expression in host cells with the use of publicly known gene recombination techniques.
  • the compounds represented by the general formula (1) may be processed into pharmaceutical compositions, which contain one or more pharmaceutically acceptable diluents, humectants, emulsifiers, dispersants, auxiliary agents, preservatives, buffers, binders, stabilizers, etc., in arbitrary forms appropriate for the desired administration route.
  • parenteral administration in particular, intravenous administration is preferable.
  • the compositions may be in the form of nonaqueous solutions, suspensions or emulsions.
  • Aseptic preparations can be obtained by, for example, sterile filtration.
  • the compounds of the present invention may be administered in an appropriate dose determined depending on the body type, age and conditions of the patient, severity of the disease, time after the onset of the disease, etc.
  • paclitaxel or its derivative for example, docetaxel
  • paclitaxel is generally given in an amount of 0.1 to 2 mg/kg.
  • Paclitaxel 50 mg, 1 equivalent was introduced into a 50 ml round bottomed flask and dissolved in pyridine (3 ml). Next, succinic anhydride (30 mg, 5.1 equivalents) was added thereto. After stirring at room temperature for 16 hours, the mixture was diluted with 30% MeCN (30 ml). Then it was filtered and purified by high performance liquid chromatography (HPLC). After freeze-drying, paclitaxel-succinic acid (51.86 mg, yield 92.2%) was obtained.
  • HPLC high performance liquid chromatography
  • EABI (4.5 mg) was introduced into a 30 ml round bottomed flask and dissolved in 80% MeCN (2 ml). Next, HOBt/DMF (21.8 mg of HOBt dissolved in 50 ⁇ l of DMF) was added thereto. After adding paclitaxel-succinic acid (5 mg, 1 equivalent) dissolved in MeCN (100 ⁇ l), WSCDI (16.3 ⁇ l, 20 equivalents) was further added thereto under ice-cooling. After stirring at room temperature for 2 hours, the mixture was diluted with 30% MeCN (15 ml). Then it was filtered and purified by HPLC. After freeze-drying. paclitaxel-(succinic acid)-EABI (5.68 mg, yield 60.1%) was obtained.
  • Pancreatic cancer-origin cells (cell line: MiaPACA), which had been incubated for 2 days, were brought into contact for 2 hours with the compound of Example 1 at various concentrations. Then, the cells were incubated in a CO 2 incubator at 37°C for 48 hours and viable cells were counted. By using paclitaxel as a control compound, the above procedure was repeated.
  • Fig. 1 shows the results.
  • the paclitaxel-(succinic acid)-EABI conjugate of the present invention shows an antitumor activity comparable to paclitaxel or even exceeding the same. This fact indicates that an anticancer agent can be targeted specifically for tumor cells wherein GRP receptor is expressed.
  • the problem of short blood half time encountering in the conventional peptide antitumor substances can be overcome.
  • these compounds of the present invention sustain the advantages (i.e., little side effects, high affinity for tumor cells and high solubility in water) of the conventional peptide antitumor substances and show improved solubility of paclitaxel derivatives and high antitumor activity thereof. Owing to these characteristics, the compounds of the present invention are highly useful as anticancer agents.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
EP98954713A 1997-11-18 1998-11-18 Composes possedant une activite antitumorale Withdrawn EP1033372A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP35602597 1997-11-18
JP35602597 1997-11-18
PCT/JP1998/005172 WO1999025729A1 (fr) 1997-11-18 1998-11-18 Composes possedant une activite antitumorale

Publications (2)

Publication Number Publication Date
EP1033372A1 true EP1033372A1 (fr) 2000-09-06
EP1033372A4 EP1033372A4 (fr) 2000-10-04

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EP98954713A Withdrawn EP1033372A4 (fr) 1997-11-18 1998-11-18 Composes possedant une activite antitumorale

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US (1) US6545125B1 (fr)
EP (1) EP1033372A4 (fr)
AU (1) AU1172599A (fr)
WO (1) WO1999025729A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038318A1 (fr) * 1999-11-24 2001-05-31 Immunogen, Inc. Agents cytotoxiques comprenant des taxanes et leur utilisation therapeutique
EP1154782A4 (fr) * 1999-02-24 2002-09-25 Uab Research Foundation Derives de taxane pour therapie ciblee contre le cancer
US6825166B2 (en) 2001-03-23 2004-11-30 Tapestry Pharmaceuticals, Inc. Molecular conjugates for use in treatment of cancer
US6903074B1 (en) 1999-06-04 2005-06-07 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Neuromedin b and somatostatin receptor agonists
US7390898B2 (en) 2002-08-02 2008-06-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
US7414073B2 (en) 2002-08-02 2008-08-19 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
CN111529716A (zh) * 2020-06-02 2020-08-14 南方医科大学 一种多肽-紫杉醇偶联物及其应用

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1367793A (zh) * 1999-06-04 2002-09-04 研究及应用科学协会股份有限公司 神经调节肽b和生长抑素受体拮抗剂
AU4267700A (en) * 2000-01-13 2001-07-19 Academia Sinica Application of somatostatin analogs to specific delivery of anti-tumor drugs into tumor cells
US20080045559A1 (en) * 2003-10-29 2008-02-21 Sonus Pharmaceuticals, Inc. Tocopherol-modified therapeutic drug compounds
WO2005042539A1 (fr) * 2003-10-29 2005-05-12 Sonus Pharmaceuticals, Inc. Composes medicamenteux a base de tocopherol modifie
EP3536347A1 (fr) 2012-09-25 2019-09-11 Advanced Accelerator Applications USA, Inc. Antagonistes grpr de détection, de diagnostic et de traitement du cancer cancers positifs au grpr
JP6114718B2 (ja) * 2014-06-17 2017-04-12 川崎重工業株式会社 軸対称体および軸対称製品の製造方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2601675B1 (fr) * 1986-07-17 1988-09-23 Rhone Poulenc Sante Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent
US5175315A (en) * 1989-05-31 1992-12-29 Florida State University Method for preparation of taxol using β-lactam
US6214345B1 (en) * 1993-05-14 2001-04-10 Bristol-Myers Squibb Co. Lysosomal enzyme-cleavable antitumor drug conjugates
WO1998013059A1 (fr) * 1996-09-27 1998-04-02 Bristol-Myers Squibb Company Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques
JP2001505194A (ja) * 1996-11-05 2001-04-17 ブリストル―マイヤーズ・スクイブ・カンパニー 分枝ペプチド・リンカー

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A.NAGY ET AL.: "Design, synthesis, and in vitro evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicidin" PNAS, vol. 94, January 1997 (1997-01), pages 652-6, XP000919308 *
A.NAGY ET AL.: "Selective coupling of methotrexate to peptide hormone carriers through a gamma- carboxamode linkage of its glutamic acid moiety: Benzotriazol-1-yloxytris(dimethylamino)pho sphonium hexafluorophosphate activation in salt coupling" PNAS, vol. 90, 1993, pages 6373-6376, XP000919313 *
See also references of WO9925729A1 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1154782A4 (fr) * 1999-02-24 2002-09-25 Uab Research Foundation Derives de taxane pour therapie ciblee contre le cancer
US6903074B1 (en) 1999-06-04 2005-06-07 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Neuromedin b and somatostatin receptor agonists
US7217819B2 (en) 1999-11-24 2007-05-15 Immunogen, Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US7276499B2 (en) 1999-11-24 2007-10-02 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US6372738B2 (en) 1999-11-24 2002-04-16 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US6706708B2 (en) 1999-11-24 2004-03-16 Immunogen, Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US7585857B2 (en) 1999-11-24 2009-09-08 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US6340701B1 (en) 1999-11-24 2002-01-22 Immunogen Inc Cytotoxic agents comprising taxanes and their therapeutic use
US7008942B2 (en) 1999-11-24 2006-03-07 Immunogen, Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US7550609B2 (en) 1999-11-24 2009-06-23 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
WO2001038318A1 (fr) * 1999-11-24 2001-05-31 Immunogen, Inc. Agents cytotoxiques comprenant des taxanes et leur utilisation therapeutique
US6436931B1 (en) 1999-11-24 2002-08-20 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US7528130B2 (en) 1999-11-24 2009-05-05 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US7476669B2 (en) 1999-11-24 2009-01-13 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US7153946B2 (en) 2001-03-23 2006-12-26 Tapestry Pharmaceuticals, Inc. Molecular conjugates for use in treatment of cancer
US6825166B2 (en) 2001-03-23 2004-11-30 Tapestry Pharmaceuticals, Inc. Molecular conjugates for use in treatment of cancer
US7414073B2 (en) 2002-08-02 2008-08-19 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
US7495114B2 (en) 2002-08-02 2009-02-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
US7390898B2 (en) 2002-08-02 2008-06-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
CN111529716A (zh) * 2020-06-02 2020-08-14 南方医科大学 一种多肽-紫杉醇偶联物及其应用
CN111529716B (zh) * 2020-06-02 2021-05-28 南方医科大学 一种多肽-紫杉醇偶联物及其应用

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Publication number Publication date
WO1999025729A1 (fr) 1999-05-27
US6545125B1 (en) 2003-04-08
EP1033372A4 (fr) 2000-10-04
AU1172599A (en) 1999-06-07

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